Traumatic brain injury (TBI) is common and frequently associated with potential long-term disability and mortality. TBI is primarily a consequence of a direct or indirect biomechanical force on brain tissues and followed by secondary injury cascade, ranging from changes in cerebral blood flow, increased intracranial pressure. Blood-brain barrier (BBB) dysfunction, edema formation, inflammation, excitotoxicity and cell death. To date, treatment strategies targeting neuronal rescue after TBI have not been clinically successful; therefore, treatments targeting the expanded vascular neural network (VNN) need to be developed not only for TBI patients but also for those with subarachnoid (SAH) and intracerebral hemorrhage (ICH). Recent studies have demonstrated that Caveolins (Cav) play a central role in several vascular diseases or injuries, with a potential protective role by inhibition of endothelial nitric oxide synthase (eNOS) and activation of c-Jun N terminal kinase (c-JNK). Both of these pathways play a detrimental role after injury in the VNN. A synthetic peptide, Cav-AP, reproduces the endogenous Cav functions by binding and inhibiting eNOS and JNK, and is now in development for cancer treatment. The role of Cav-1 will be investigated in a TBI rat model, by: i) decreasing Cav-1 with siRNA; and ii) mimicking Cav-1 functions by injection of Cav- AP after injury. We will also investigate the molecular mechanisms by testing: i) the level of activation of eNOS and JNK after TBI and Cav-AP treatment within the VNN, ii) with injection of an eNOS inhibitor (LNIO) and iii) treatment by a peptide D-JNKI inhibitor of the JNK pathway. Finally, Cav-AP will be tested as a potential treatment in SAH and ICH. Understanding the roles of Cav-1, eNOS and the JNK pathway in brain vascular system will provide avenues for development of therapeutic targets towards the VNN in hemorrhagic diseases.